Electroporation device

ABSTRACT

An electroporation device for injecting a product into a ciliary muscle of an eye includes a support having a spherical support contact surface extending along a virtual sphere having a radius between 10 and 15 mm, a first electrode comprising a curved invasive electrode needle, a second electrode having an electrically conductive electrode contact surface, and an injection needle.

This application is a continuation application of U.S. patentapplication Ser. No. 15/567,002 filed Oct. 16, 2017, which is the U.S.National Phase of PCT Application No. PCT/EP2016/058138 filed Apr. 13,2016, and which in turns claims priority to European Patent ApplicationNo. 15305548.8 filed Apr. 14, 2015. The entire disclosures of theseapplications are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a device to electroporate a productinto an eye, and in particular in the ciliary muscle.

PRIOR ART

WO 2006/123248 describes a device for administering a product byelectroporation.

WO 00/07530, WO 2007/052730 and WO 2006/052557 describe injectiondevices.

It is an object of the invention to make available a new electroporationdevice which permits

-   -   a precise and stable positioning of the electrodes;    -   a limited risk of injury; and    -   the generation of an efficient large electrical field.

SUMMARY OF THE INVENTION

To this end, the invention proposes an electroporation device forinjecting a product into an eye, and in particular into a ciliary muscleof an eye, said device comprising:

-   -   a support having a support contact surface extending along a        virtual sphere having a radius between 10 and 15 mm, so as to        match the outside surface of the eye,    -   a first electrode comprising an invasive electrode needle,    -   a second electrode having an electrically conductive electrode        contact surface,    -   optionally an injection needle,

According to a first main embodiment, the support comprises an insertionguide configured to guide a sliding of said electrode needle and/orinjection needle along a respective insertion axis, so that the angle ωbetween said insertion axis and a plane P_(S) tangential to the virtualsphere at the insertion point is less than 40°, preferably less than35°, preferably less than 30°, preferably less than 28°, and/or greaterthan 10°, preferably greater than 15°, preferably greater than 20°, theinsertion point being the point where said insertion axis crosses saidvirtual sphere.

The inventors have discovered that this configuration enables a veryprecise and efficient electroporation for a product injected into theciliary muscle. In particular, it enables the electrode needle to extendin front of the electrode contact surface, substantially parallelly tothe electrode contact surface.

Preferably, the angle ω for the insertion axis of an injection needle isless than 25°, preferably less than 23°.

Preferably, the angle ω for the insertion axis of at least one electrodeneedle is greater than 25°. In a preferred embodiment, the angle ω issubstantially the same for all the electrode needles.

Preferably, the angle between said insertion axis and a plane tangentialto the electrode contact surface, preferably at least a planeperpendicular to the main axis of the electrode contact surface,preferably any plane tangential to the electrode contact surface,preferably a general plane of the electrode contact surface is less than20°, preferably less than 15°, preferably less than 10° or less than 5°.Therefore, the insertion axis is substantially parallel to the electrodecontact surface.

Preferably, the support comprises at least two, or exactly three, four,five or more electrode insertion guides, preferably parallel to eachother, which extend in a common plane which defines with a planetangential to the electrode contact surface, preferably at least a planeperpendicular to the main axis of the electrode contact surface,preferably any plane tangential to the electrode contact surface, anangle less than 20°, preferably less than 15°, preferably less than 10°or less than 5°. The electrode needles can therefore define a net,preferably a grid, extending in front of and substantially parallelly tothe electrode contact surface. Advantageously, the electroporation ishomogeneous.

According to a second main embodiment, at least along a part of itslength, the electrode needle is flattened and has

-   -   a width W₁₄ comprised between 0.2 and 2.0 mm, and    -   a thickness T₁₄ such that the ratio W₁₄/T₁₄ being greater than        3.

According to a third main embodiment, the support comprises an insertionguide configured to guide a sliding of said electrode needle and/orinjection needle along a respective insertion axis, and the supportdefines a circular rim, preferably an open circular rim, i.e. defining apart of a circle, having an axis X and a radius of greater than 5 mm andof less than 8 mm, so as to match the limbus of an eye, and theinsertion axis defines, at the insertion point, an angle α less than50°, preferably less than 45°, preferably less than 40°, with a planeP_(Cy′) tangential to a cylindrical surface Cy′ of axis X containing theinsertion point and having a circular base.

Preferably, the angle α for the insertion axis of an injection needle isless than 35°, preferably less than 30°, preferably less than 28°,and/or greater than 10°, preferably greater than 20°, preferably greaterthan 25°.

Preferably, the angle α for the insertion axis of at least one electrodeneedle is less than 35°, preferably less than 33°, and/or greater than10°, preferably greater than 20°, preferably greater than 25°,preferably greater than 30°.

Preferably, the angle α for the insertion axis of at least one electrodeneedle is less than 38°, and/or greater than 30°, preferably greaterthan 35°.

Preferably, the support comprises at least two electrode insertionguides, preferably parallel to each other, which extend in a commonplane which defines with the plane of the rim an angle Ω which isgreater than 40°,greater than 45°, preferably greater than 50°, and/orless than 80°, preferably less than 70°, preferably less than 60°,preferably less than 55°.

According to a fourth main embodiment, the first electrode and/or theinjection needle comprises a guiding rod, extending parallel to theelectrode needle(s) and/or to the injection needle, respectively, andthe support comprises corresponding rod insertion guide(s).

Preferably, the insertion guide(s) is(are) holes which do not cross thevirtual sphere on which the support contact surface extends.

Preferably, the guiding rod(s) of the first electrode and/or theinjection needle extends beyond the tip of the electrode needle(s) ofthe first electrode and/or of the injection needle, respectively, by adistance which is preferably greater than 2 mm and less than 5 mm.

Preferably, the largest transversal dimension of a guiding rod isgreater than 0.5 mm, preferably greater than 0.8 mm, preferably greaterthan 0.9 mm, and/or less than 2.0 mm, preferably less than 1.5 mm,preferably less than 1.2 mm.

Preferably, the device comprises a needle stop that is able to limit theaxial movement of the guiding rod. Preferably, the needle stop makesimpossible the complete extraction of the guiding rod out of thecorresponding insertion guide, i.e. hinders any dismounting of theguiding rod from the support.

The inventors have discovered that the features of these mainembodiments are advantageous for the efficiency of the electroporation.

The characteristics of the different main embodiments of the invention,optional or not, as well as the optional characteristics in thefollowing description may be combined or not. For instance, in the firstmain embodiment, the first electrode may be a flattened electrode ornot.

Preferably, whatever the main embodiment, the device comprises one orseveral of the following optional and preferred characteristics:

-   -   The insertion axis of the electrode needle defines an angle with        a plane perpendicular to the main axis of the electrode contact        surface, said angle being less than 20°, preferably less than        10°, preferably less than 5°;    -   Preferably, all the electrode insertion guides extend parallel        to each other in a common plane;    -   The first electrode comprises a plurality of parallel invasive        electrode needles extending in a common plane, the angle between        said plane and the general plane in which the second electrode        extends being less than 10°;    -   The support defines a circular rim, preferably an open circular        rim, having an axis X and a radius of greater than 5 mm and of        less than 8 mm, so as to match the limbus of an eye, said rim        being interrupted by at least one notch, preferably located in a        portion of the rim which extends along an angular sector less        than 120° and centred on a median plane of the second electrode;    -   In a close position, the portion of said electrode needle which        extends in front of the electrode contact surface is greater        than 1 mm, preferably greater than 2 mm, preferably greater than        3 mm, preferably greater than 5 mm, preferably greater than 6        mm.    -   The length of said electrode needle is determined so that, in a        front view of the second electrode, the inserted electrode        needle faces the electrode contact surface and extends, in a        close position, so as to completely cross, i.e. “bar”, the        electrode contact surface defined by the second electrode;    -   The surface area of the electrode contact surface is greater        than 6 mm² and less than 20 mm²;    -   The electrode contact surface preferably defines a spherical        contact surface which preferably extends on the same virtual        sphere as the support contact surface;    -   Preferably, the complete contact surface defined by the support        contact surface and the electrode contact surface has the shape        of an open circular band;    -   The support presents the general shape of an open ring, so that        it presents a gap between a first end and a second end, and,        preferably,    -   the support is made in a material which exhibits a plastic        behaviour, so that the support may be manually plastically        deformed to modify the distance between said first and second        ends, and/or    -   said gap is preferably disposed substantially opposite to the        second electrode, and/or    -   the support preferably comprises two holding posts positioned at        said ends of the support;    -   The support comprises prepositioning guide(s) configured to        guide said electrode needle and/or said injection needle into a        position wherein said electrode needle and/or said injection        needle is(are) in line with an insertion axis of a corresponding        insertion guide;    -   The support contact surface and/or the electrode contact surface        are defined by a material which is biocompatible, and in        particular, which is can be put in contact with surface of the        eye without prejudice;    -   The support contact surface and/or the electrode contact surface        are defined by a material which is a polycarbonate, for instance        sold by Bayer;    -   The electrode contact surface is defined by brass;    -   The device comprises        -   an injection needle, and        -   electrode insertion guide and injection needle insertion            guide configured to guide a sliding of said electrode needle            and injection needle along respective electrode needle            insertion axis and injection needle insertion axis, any            plane perpendicular to said electrode needle insertion axis            being parallel to any plane perpendicular to said injection            needle insertion axis, and, preferably parallel to the main            axis of the electrode contact surface;    -   In a close position of the injection needle, the maximal depth        of the injection needle under the virtual sphere is between 0.8        mm and 1.0 mm, and/or, in a close position of the electrode        needle, preferably of any electrode needle, the maximal depth of        the electrode needle under the virtual sphere is between 1.5 mm        and 1.8 mm;    -   The device comprises a reservoir containing said product and an        injection needle in fluid communication with said reservoir,        said product being a therapeutic nucleic acid of interest,        preferably a desoxyribonucleic acid molecule or a ribonucleic        acid molecule.

The invention also concerns an electroporation method for injecting aproduct into an eye, in particular in the ciliary muscle of an eye, bymeans of a device according to the invention, said method comprising thefollowing steps:

-   -   a) placing the electrode contact surface on the outside surface        of said eye, preferably so that a rim of the support bears on        the limbus of said eye (edge of the cornea),    -   b) inserting the electrode needle(s) of the first electrode into        corresponding insertion guide(s) of the support preferably so        that the ciliary muscle extends, at least partially, between the        electrode needle(s) of the first electrode and the second        electrode,    -   c) before or after step b), preferably after step b), inserting        an injection needle into the eye, preferably while being guided        by a corresponding insertion guide, so that its tip preferably        reaches the ciliary muscle of said eye,    -   d) injecting said product into the eye,    -   e) generating an electrical field between the electrode        needle(s) of the first electrode and the second electrode, the        electrical field being adapted to promote electroporation.

Definitions

When a needle is mobile and guided by the support, its positioncorresponding to its full insertion is called the “close position”. Inthe present description, unless otherwise stated, any position of thefirst electrode is referring to the close position and any position ofthe second electrode is referring to the position of the secondelectrode when it is attached to the support and ready for service.

The “service position” corresponds to the configuration adapted forelectroporation of the product, in particular in the ciliary muscle: Theelectrode contact surface and the support contact surface bear on theeye, with the first electrode in its close position.

A “flattened” needle does not mean that the needle is necessarily flat,i.e.

extends in a plane. It means that the needle has a thickness which ismuch smaller that its width, preferably at least 5 times smaller.

The “insertion point” of a needle is the point where, in the closeposition, said needle crosses the virtual sphere bearing the supportcontact surface. When this needle is guided, the insertion pointcorresponds to the point where the insertion axis crosses the virtualsphere. Preferably, the insertion points correspond to an outlet orificeof an insertion guide.

A “spherical contact surface” means a substantially spherical contactsurface, preferably so as to correspond to the shape of the anterior orposterior part of the outside surface of an eye.

The “main axis” of a surface is the direction perpendicular to saidsurface passing through its centre.

A “quadrant of a hemisphere” designates a quarter of the surface of thishemisphere obtained by cuts in two perpendicular planes that intersectalong the main axis of the hemisphere.

“First” and “second”, or “upper” and “lower”, or “right-hand” and“left-hand” are used to distinguish corresponding elements, but do notlimitate the invention.

In the present description, unless otherwise stated, “comprising a”should be understood as “comprising at least one”.

BRIEF DESCRIPTION OF THE FIGURES

Other features and advantages of the invention will become clear uponreading the non limitative following detailed description and byexamining the non limitative attached drawing, in which:

FIGS. 1a and 1b show, in perspective and along the transverse plane P1,a first embodiment of a device according to the invention;

FIG. 2a shows, in perspective, a second embodiment of a device accordingto the invention;

FIGS. 2b and 2c show, view from above, along the axis X, the secondembodiment of FIG. 2a and a variation of this second embodiment,respectively;

FIGS. 3a and 3a ′ show, in a cross section, a third embodiment of adevice according to the invention,

FIGS. 4a-4e show, in different views, a fourth embodiment of a deviceaccording to the invention,

FIGS. 5a-5f represent the most preferred embodiment of the invention, ina front view, in a right view, in a left view, in cross-section AA, incross-section BB and in perspective, respectively,

FIG. 5g represents a preferred embodiment of the first electrode,

FIGS. 6a-6h represent another most preferred embodiment of theinvention, in a right view for FIGS. 6b and 6d , and in differentcross-sections in the other figures.

In the embodiment of FIG. 3a , the side view of the electrode needle isobserved perpendicularly to the plane in which, in the close position,the inserted part of the electrode needle substantially extends andwhich is perpendicular to the rim 20.

In the various figures, identical reference signs are used to designateidentical or similar elements.

DETAILED DESCRIPTION

The figures represent examples of devices according to the invention.

Each of these devices comprises a first electrode 10, a second electrode12, and a support 16. The second electrode defines an electrode contactsurface 17 designed to contact the surface of the eye.

Support The support defines a spherical support contact surface 18. Thissupport contact surface extends along a virtual sphere S correspondingto the outside surface of an eye O so that, in the service position, itcan bear on the outside surface of said eye.

Preferably, the support 16 also defines a circular rim 20, having anaxis X, which partially defines the limit of the support contact surface18.

General Shape

Preferably, the support has the general shape of a ring around the axisX, as represented in FIG. 2a , or of a part of a ring as represented inFIG. 4 or in FIG. 5.

In FIG. 4, the support 16 has a general shape of a ring which isinterrupted by a gap 23 separating a first end 24 a and a second end 24b. Said gap is preferably greater than 0.5 mm, preferably greater than 1mm, and/or less than 8 mm, less than 6 mm, less than 5 mm, less than 4mm.

Preferably, when the ring is interrupted, as in the embodiment of FIG.4, the support is made in a material which exhibits a plastic behaviour,so that the support may be manually plastically deformed to modify thedistance between said first and second ends. Advantageously, the support16 may be deformed to different sizes of eyes.

The gap is preferably disposed substantially opposite to the secondelectrode, which makes the manipulation of the support easier.

Preferably, the ring extends laterally over an angle sector α₂₀ ofgreater than 45°, preferably greater than 60°, preferably greater than80°, preferably greater than 100°, preferably greater than 120°,preferably greater than 130°, preferably greater than 135°, and/or lessthan 180°, preferably less than 170°, preferably less than 160°,preferably less than 150°, preferably less than 140° (see FIG. 5f ).

The support preferably comprises a holding post, preferably at least twoholding posts 25, preferably four holding posts 25, preferablypositioned at the first and second ends of the support, respectively.The holding posts make the manipulation of the support easier. Theholding posts 25 are on the upper surface of the support, preferably ona portion of the outside surface which is opposite to the supportcontact surface 18, and are preferably at least partly located on thepart of the support which is opposite to the second electrode.

The support contact surface 18 preferably bears one, preferably severalspikes 26 which are protruding from said surface and designed so as tolimit the sliding of the support on the eye. The support preferablycomprises more than 2, more than 5, more than 10, more than 20 spikes26. The height of said spikes is preferably more than 0.1 mm and/or lessthan 0.5 mm or less than 0.3 mm.

In one embodiment, the support is designed to be able to keep theeyelids open during the stage of penetration of the electrode needle.

The support may also bear elastic means, for instance a spring,configured to force the first electrode and/or an injection needletoward the close position and/or to push the second electrode on thesurface of the eye.

The support 16 is preferably in a polymeric material. It is preferablyin a material which is not electrically conductive.

The support is preferably made of a transparent material for a betterobservation by the user.

The support can be used for manipulation of the device. As representedin FIG. 5, the support can in particular comprise a handle 31 allowingthe injection device to be gripped, for example, between a thumb and anindex finger of one hand. Manipulation of the device is made much easierin this way.

Preferably, the handle extends along an axis Δ₃₁ which is inclined,relatively to the plane of the rim, with an angle ω₃₁ greater than 25°,preferably greater than 30° and/or less than 45°, less than 40°, lessthan 35°.

When the first electrode 10 comprises several coplanar electrode needlesguided by corresponding coplanar electrode insertion guides, the handlepreferably extends substantially along an axis Δ₃₁ substantiallyperpendicular to the plane containing said electrode insertion guides.

The length I₃₁ of the handle 31 is preferably greater than 5 mm or 8 mmand preferably less than 50 mm, 30 mm, 20 mm, 15 mm.

Support Contact Surface

The width of the support contact surface 18 may be constant or not. Inthe embodiment of FIG. 4, the width of the support contact surface islarger in the neighbourhood of the second electrode than in theneighbourhood of the two ends 24. Advantageously, the risk of injury islimited.

The radius of curvature R of the support contact surface 18 preferablyranges between 10 mm and 15 mm, preferably between 11 mm and 14 mm,preferably between 12 mm and 13 mm, and is preferably about 12.5 mm. Thestability of the support on the eye is therefore greatly improved.

In one embodiment, the support contact surface 18 has a surface area ofgreater than 50 mm², preferably of greater than 100 mm², preferably ofgreater than 120 mm², preferably of greater than 140 mm², preferably ofgreater than 150 mm², preferably of greater than 160 mm², and/or of lessthan 200 mm², preferably of less than 180 mm².

The support contact surface 18 may be solid or can be locallyinterrupted by holes.

In a preferred embodiment, the support contact surface 18 is interruptedby a hole 19 for the introduction of the second electrode (see FIGS. 4and 5).

Preferably, the support contact surface 18 does not extend over morethan one quadrant of a hemisphere.

In a preferred embodiment, the support contact surface 18 has thegeneral shape of a circular band, preferably an open circular band.

Seen from the front, the support contact surface 18 can have asubstantially parallellepipedal contour, for example a rectangularcontour, or a substantially trapezoidal contour.

The support contact surface 18 can have two large sides and two smallsides. The large sides can in particular form rounded corners with thesmall sides. The length of the small sides can be greater than 3 mm,preferably greater than 4 mm, and/or less than 10 mm, preferably lessthan 8 mm, preferably less than 7 mm, preferably less than 6 mm. Thelength of the large sides can be greater than 10 mm, preferably greaterthan 12 mm, preferably greater than 14 mm and/or less than 20 mm,preferably less than 18 mm, preferably less than 16 mm. Preferably, thesupport is configured so that, when the support contact surface 18 bearson the surface of the eye, the support can only contact the surface ofthe eye by way of the support contact surface 18.

Rim

The rim 20 has the shape of an arc of a circle C₂₀ (including a completecircle) having an axis X and a radius R₂₀ of greater than 5 mm,preferably of greater than 5.5 mm, preferably of greater than 5.8 mm,and of less than 8.0 mm, preferably of less than 7.0 mm, preferably ofless than 7.5 mm, preferably of less than 6.0 mm. Such a rim has a shapesubstantially corresponding to the limbus L_(i) of the eye. It may beplaced in contact with this limbus, so as to encircle at leastpartially, possibly completely, said limbus.

The stability of the support is greatly improved when the rim 20 isdesigned to bear on the limbus of the eye.

Preferably, the second electrode does not define, even partly, any suchrim. In a preferred embodiment, only the support defines a rimconfigured to bear on the limbus.

The rim 20 may have the shape of a complete circle, as in FIG. 2a .Advantageously, in the service position, the stability of the device isincreased. However, preferably, the rim 20 is open, i.e. is not closedon itself, as represented in FIG. 4. Preferably, the rim 20 is largelyopened, as represented in FIG. 5, which makes its handling easier.

The length of said arc of a circle is preferably greater than 5 mm,preferably greater than 10 mm, preferably greater than 12 mm, preferablygreater than 13 mm, greater than 14 mm, and/or preferably less than 45mm, preferably less than 40 mm, less than 35 mm, preferably less than 30mm, preferably less than 25 mm, preferably less than 20 mm, preferablyless than 17 mm, preferably less than 15 mm.

The support is preferably provided with a flexible skirt 22 extendingalong said rim (see FIG. 2a ), the flexible skirt being preferably madeof a material chosen in the group formed of polymers of silicone,conductive sponge, in particular synthetic sponge, polyester,polyorthoester, polymethyl methacrylate or of any other flexiblemedical-grade polymers.

Preferably, the rim is interrupted by at least one notch 21, preferablyat least two notches, preferably three notches. The notches 21 areconfigured so that the physician may see the limbus of the eye throughthem when positioning the support onto the eye. At least one notch,preferably all the notches are located in the neighbourhood of thesecond electrode.

In FIGS. 4 and 5, the support comprises two and three notches 21,respectively, which interrupt the rim 20 in the neighbourhood of thesecond electrode. Indeed, it is in this region that the positioning ofthe support is of utter importance.

Preferably, the notch(es) (is) are located in a portion of the rim whichextends along an angular sector α₂₁ less than 120°, preferably less than100°, said angular sector being preferably centered on a median plane Mof the second electrode (see FIG. 4d ).

The positioning of the device on the eye is advantageously made simplerand more precise.

Electrodes

By definition, the first and second electrodes are designed to beelectrically connected to first and second terminals, respectively, ofan electrical generator.

The first and second electrodes comprise non represented first andsecond connectors for the electrical connection to said first and secondterminals, respectively. The electrical generator is adapted to polarizedifferently said first and second electrodes so as to generate anelectrical field enabling electroporation.

A device according to the invention may also include such an electricalgenerator.

First Electrode

The first electrode 10 may comprise one or several, preferably three,four or five, preferably parallel, preferably coplanar, preferablyrectilinear electrode needles 14. The electrode needles are preferablyfixed to each other so as to form a fork or a comb, as represented inFIG. 4a or FIG. 5g . The distance between the axis of two adjacentelectrode needles is preferably greater than 0.5 mm, preferably greaterthan 0.6 mm, preferably greater than 0.7 mm, preferably greater than 0.8mm, and/or less than 5 mm, preferably less than 3 mm, preferably lessthan 1.5 mm, preferably less than 1.2 mm, preferably less than 1.0 mm,preferably less than 0.9 mm.

Preferably, all the electrode needles have the same structure. In thefollowing description, only one electrode needle 14 is described, butone or several of its features may be applied to any electrode needle ofa first electrode comprising a plurality of electrode needles. In apreferred embodiment, all the electrode needles have the same structure.

Preferably, the length l₁₄ of an electrode needle 14 is greater than 8mm, preferably greater than 10 mm, preferably greater than 11 mm, and/orless than 15 mm, preferably less than 14 mm, preferably less than 13 mm(see FIG. 3a ′ and 4 a).

Preferably, the insertion length l_(14i) of an electrode needle,preferably of any electrode needle, i.e. which extends inside thevirtual sphere S in the close position, is greater than 5 mm, preferablygreater than 7 mm, preferably greater than 8 mm, and/or less than 13 mm,preferably less than 12 mm, preferably less than 11 mm (see FIG. 3a ′).

Preferably, the diameter of an electrode needle 14 is less than 0.5 mm,preferably less than 0.4 mm, preferably less than 0.35 mm. Thischaracteristic is particularly advantageous when the electrode needle isinserted into the eye substantially tangentially to the surface of theeye, as in the embodiment of FIG. 4 or FIG. 5.

Preferably, the diameter of an electrode needle 14 is greater than 0.2mm, preferably greater than 0.3 mm. Advantageously, the electrode needleis thereby stiff enough to be inserted in the eye, and in particularsubstantially tangentially to the surface of the eye.

For the same reason, the tip 27 of the electrode needle 14 is preferablybevelled for facilitating the penetration of the electrode needle intothe eye, as represented in FIG. 1a and 3 a.

In an embodiment, any electrode needle 14 comprises an insulated part 14a which outside surface is electrically insulated, and a non insulatedpart 14 b, preferably extending from the insulated part to the tip 27 ofthe electrode needle.

The insulated part 14 a may be insulated, for example, by means of aninsulating cover, preferably so that the electrically insulated part ofsaid electrode needle may penetrate of at least 0.4 mm, at least 0.6 mmor at least 0.8 mm into the virtual sphere S in the close position.

As illustrated in FIG. 1, the electrode needle 14 may comprise aflattened part, i.e. is such that the ratio of its width and itsthickness W₁₄/T₁₄ is greater than 3, preferably greater than 5, greaterthan 7, greater than 10, greater than 15, greater than 20, and/or lessthan 30 or less than 25. Preferably, the width W₁₄ is comprised between0.15 and 2.0 mm, preferably greater than 0.20 mm, and/or the thicknessT₁₄ is comprised between 0.15 and 0.5 mm, preferably greater than 0.20mm.

The flattened part preferably represents more than 50%, more than 60%,more than 70%, more than 80% or more than 90% of the length of theinsertion part which is to be inserted in the eye, i.e. which mayprotrude inside the virtual sphere S bearing the support contact surface18.

Preferably, the flattened part extends up to the tip 27 of the insertionneedle and/or along all the length of the electrically conductive part14 a, and even along all the length of the insertion part, andpreferably all along the length of the electrode needle.

The flattened part preferably comprises upper and lower large faces 14 ₁and 14 ₂, and right-hand and left-hand lateral faces 14 ₃ and 14 ₄,defining the thickness of the flattened part, i.e. the maximal distancebetween the two large faces.

The flattened part may be curved along its length (see FIG. 1a ), and/oralong its width (see FIG. 1b ).

The flattened part 14 may have the shape of a chute or of a part of asphere.

In a preferred embodiment, the upper large face 14 ₁ at least partiallyextends substantially parallel to the contact surface of the secondelectrode.

In particular, at least in the region facing the electrode contractsurface, the upper large face 14 ₁ may have the shape of a sphere havingthe same centre as the virtual sphere S. Advantageously, the homogeneityof the electrical field between the first and second electrodes isimproved if the electrode contact surface extends along said virtualsphere. The upper large face 14 ₁ may also have a length and/or a widthcorresponding to that of the second electrode.

The flattened part 14 may have constant or variable length and/or widthand/or thickness. In particular, it may be bevelled when the electrodeneedle is observed laterally, and/or from above, i.e. as observedperpendicularly to the large faces.

Preferably, in the active region of the upper large face, i.e. theregion facing the second electrode in the close position, the thicknessand/or the width of the flattened part is substantially constant.

Second Electrode

In FIGS. 2b and 2c , the second electrode is represented with a dashedline.

The electrode contact surface 17 preferably extends along the samevirtual sphere S as the spherical support contact surface 18 of thesupport. It matches the outside surface of an eye O so that, in theservice position, it can bear on the outside surface of said eye O.

It may be an electrically conductive layer covering at least part of,preferably the whole surface of the support contact surface 18, as inthe embodiments of FIGS. 2 and 3.

In the embodiments of FIGS. 4 and 5, the second electrode is notintegral with the support, i.e. is a part which is initially independentof the support, then mounted onto the support.

Preferably, as represented in FIG. 4a , the second electrode can beremoved, i.e. detached, from the support.

When the second electrode is to be mounted on the support (FIGS. 4 and5), the support, in particular an handle of the support, is preferablyconfigured to guide this mounting. In particular, the support may definea tube (FIG. 4) or of a gutter (FIG. 5), in which the second electrodemay slide until an assembled position. Preferably, the support comprisesan elastic tongue 37 or claw configured to fix the second electrode onthe support in an assembled position, possibly in a reversible manner(see FIG. 5d ).

The second electrode 12 is preferably a plate contact electrode made ofan electrically conductive material.

The second electrode may also comprise a set of spikes, preferablyextending perpendicularly to its contact surface 17. These spikes may besimilar to the spikes 26 of the support. Preferably, the secondelectrode does not comprise any spike. Preferably, it is smooth.

The second electrode may define the circular rim 20. However, asrepresented in FIG. 4, the rim 20 is preferably defined by the support.

The electrode contact surface 17 is preferably substantially surroundedby the support contact surface 18.

Preferably, the distance d₁₈ between the rim 20 and any point of theelectrode contact surface 18 is greater than 2 mm, preferably greaterthan 2.5 mm, preferably greater than 3 mm, preferably greater than 3.5mm, preferably greater than 4.0 mm, and/or less than 6 mm, preferablyless than 5 mm, preferably less than 4.5 mm (see FIG. 6e ).

Preferably, the electrode contact surface does not extend over more thanone quadrant of a hemisphere.

Preferably, the second electrode extends within an angular sector α₁₂around the axis X (see FIG. 2c ) which is less than 90°, preferably lessthan 60°, preferably less than 50°, preferably less than 45°, preferablyless than 35°, preferably less than 30°, and/or preferably greater than10°, preferably greater than 15°, preferably greater than 20°.

The surface area of the electrode contact surface is preferably greaterthan 3 mm², greater than 4 mm², greater than 5 mm², greater than 6 mm²,greater than 8 mm², greater than 10 mm², greater than 11 mm², greaterthan 12 mm², greater than 15 mm², greater than 17 mm², and/or less than90 mm², less than 60 mm², less than 30 mm², less than 20 mm².

In a front view, the electrode contact surface has preferably asubstantially rectangular shape. In said front view, the length l₁₂ ofthe second electrode is preferably greater than 3 mm, greater than 4 mm,greater than 5 mm, and/or less than 8 mm, less than 7 mm. In said frontview, the width w₁₂ of the second electrode is preferably greater than 1mm, preferably greater than 2 mm, and/or less than 4 mm.

Injection Needle

Preferably, the device comprises an injection needle 42.

The injection needle may be part of the first electrode and/or of thesecond electrode and/or of the support. In particular, it may be in anelectrically conductive material so as to constitute or be a part of thefirst and/or second electrodes. In particular, an electrode needle 14 ofthe first electrode may be an injection needle.

On the contrary, and preferably, the injection needle may be independentof the first and second electrodes, as in FIG. 4 or 5.

Preferably, the injection needle is configured so that it can onlypenetrate into an eye so that the maximal depth p₄₂ of the injectionneedle under the outside surface of the eye is comprised between 0.6 mmand 1.3 mm, preferably greater than 0.7 mm, preferably greater than 0.8mm, preferably greater than 0.85 mm, and/or less than 1.2 mm, preferablyless than 1.1 mm, preferably less than 1.0 mm, preferably less than 0.95mm.

The injection needle may in particular have one or severalcharacteristics of the injection needle disclosed in WO 2009/122030, orU.S. Ser. No. 12/921,979, incorporated by reference.

Preferably, the insertion length of the injection needle is greater than2 mm, preferably greater than 3 mm, preferably greater than 3.5 mm,preferably greater than 4.0 mm, and/or less than 7.0 mm, preferably lessthan 6.0 mm, preferably less than 5.5 mm.

Preferably, the ratio of the insertion length of the injection needle onthe maximal insertion length of any electrode needle is between 0.3 and0.7, preferably between 0.4 and 0.6, preferably about 0.5.

Preferably, the insertion length of the injection needle and theposition of a corresponding injection needle insertion guide aredetermined so that, in the close position of the injection needle and ofa plurality of electrode needles, the tip of the injection needle is atthe centre of a grid defined by the electrode needles inside the virtualsphere S, when observed along the main axis Δ₁₇ of the electrode contactsurface 17 (see FIG. 6g ).

The injection needle may comprise an injection channel 36, having one ormore ejection orifices 38.

One or several, or all the ejection orifices 38 may open out axiallyrelative to the main axis of the injection needle, as represented inFIG. 3a , or not. In particular, one or several, or all the ejectionorifices 38 may open out on a large face (as represented in FIG. 1a )and/or on a lateral face of a flattened part of an electrode needle.

The ejection orifices are preferably homogeneously spread on a largeface of the flattened part.

As represented in FIG. 1 a, an injection channel 36 may be fixed on theelectrode needle 14, and in particular on a large face of a flattenedelectrode needle.

The ejection orifice(s) may open out radially.

For a flattened electrode needle in particular, the injection channel 36may be defined, at least partially, by a wall in a non metallicmaterial, in particular a polymer, for example chosen in the groupformed of polymers of silicone, polyester, polyorthoester, polymethylmethacrylate and any other flexible medical-grade polymers. Theinjection channel 36 is preferably defined by a wall made in silicone.

Preferably, according to the embodiment of FIG. 4, the device comprisesonly one single injection needle 42, preferably provided with a needlestop to limit the insertion into the eye.

Guidance of the Needles

The support 16 may be provided with one or a plurality of insertionguides 28.

A needle, i.e. an electrode needle 14 or an injection needle 42, cantherefore be mobile and guided between an extreme (i.e. limited by anabutment) close position and a remote position in which it is protrudingand not protruding, respectively, inside from the support contactsurface 18. The device may comprise a mechanism to automatically changethe position of a needle, and in particular of an electrode needle 14,from the remote position to the close position.

The guided movement of a needle may be in rotation and/or intranslation.

Preferably, an insertion guide 28 is configured so as to hinder anyrotation of the corresponding needle around its longitudinal axis. Asrepresented in FIG. 2a , the cross section of an insertion guide 28 maybe asymmetric and complementary to that of the corresponding needle,e.g. rectangular as represented.

In an embodiment, the guidance results from the contact between theinserted needle and the surface of the hole of the support into whichthe needle is inserted, as represented in FIG. 4.

The support preferably comprises an electrode insertion guide 28 a toguide, by contact with an invasive electrode needle, the insertion of aninvasive electrode needle, and/or an injection needle insertion guide 28b to guide, by contact with an injection needle, the insertion of saidinjection needle.

The cross-section of an insertion guide 28 a or 28 b preferably matchesthe cross-section of the corresponding electrode needle or injectionneedle, respectively.

Preferably, an insertion guide 28 a or 28 b has the shape of a holewhich goes through the support, exiting on its contact and outsidesurfaces through corresponding outlet orifice 30 and inlet orifice 32,respectively.

The largest and/or the smallest dimension(s) of the cross-section of thehole is preferably less than 0.5 mm, preferably less than 0.4 mm,preferably less than 0.35 mm, and/or preferably greater than 0.2 mm,preferably greater than 0.3 mm.

Preferably, the hole has a shape of a tube, having preferably a constantcross-section along its length. The length of an insertion guide ispreferably greater than 0.5 mm, preferably greater than 1 mm, preferablygreater than 2 mm.

The cross-section is preferably circular.

Alternatively or in addition, in a preferred embodiment, the firstelectrode and/or the injection needle comprises at least one, preferablyat least two guiding rods 39, extending parallel to the electrodeneedle(s) and/or to the injection needle, respectively, and the supportcomprises corresponding rod insertion guides 28 c (see FIG. 5g ).

The length l₃₉ of a guiding rod is preferably greater than 12 mm,preferably greater than 14 mm, and/or less than 20 mm, preferably lessthan 17 mm, preferably less than 16 mm.

Preferably, the rod insertion guides 28 c are holes which do notpenetrate into the virtual sphere S on which the support contact surface18 extends.

Therefore, when the support contact surface 18 bears on the outsidesurface of an eye O, the guiding rods cannot go through the supportcontact surface 18, and consequently cannot penetrate into the eye.Advantageously, the guiding length, i.e. the length of the insertionguide 28 c can be increased.

Preferably, a guiding rod, or any guiding rod is provided with a rodstop 40 that is able to limit the sliding movement of said guiding rod39 outside the corresponding rod insertion guide 28 c, as represented inFIG. 6c . In this figure, the rod stop 40 abuts on the support 16, inparticular in the bottom of a sliding rail 41.

Preferably, only one guiding rod is provided with a rod stop 40.

Preferably, only one guiding rod is provided for the set of all the rodstops 40.

Preferably, the sliding of the rod stop 40 in the support is not guided.

The guiding rod 39 is therefore mobile from a retracted position (FIGS.6a and 6c ) and an inserted position (FIGS. 6g and 6h ), wherein theneedle(s) guided by the guiding rod 39, i.e. the four electrode needlesin the embodiment of FIG. 6, is (are) outside the virtual sphere S (seeFIG. 6a ) and at least partly inside the virtual sphere S (see FIG. 6g), respectively.

In the retracted position, the support contact surface canadvantageously be placed so as to bear on the eye, before the insertionof the guided needle(s), without any risk of injury.

Advantageously, a rod stop 40 hinders the dismounting of thecorresponding guiding rod 39 from the support. In any position, and inparticular in the retracted position, the guiding rod is thereforealways at least partly inside the corresponding rod insertion guide.Consequently, for the insertion of the guided needle(s) into the eye,there is no need for any previous introduction of a guiding rod into acorresponding rod insertion guide. The insertion of the guided needle(s)is therefore made easier.

In addition, there is no risk that the tip of said guided needle(s)could touch the support, and possibly extract some part of the supportand introduce it into the eye. Alternatively or in addition, for thesame purpose, an insertion guide, and in particular an injection needleinsertion guide 28 b, may be defined with a metal or a ceramic material.A metal or ceramic cover may be provided on the support or the insertionguide may be defined with a metal or ceramic tube or part 43 (see FIG.6g ).

Preferably, as represented in FIG. 6a , the tip 27 of (a) guidedneedle(s) is (are) inside the support in the retracted position of theguiding rod. Advantageously, the risk of injury is therefore limited.

Preferably, the guiding rod(s) of the first electrode and/or theinjection needle extends beyond the tip of the electrode needle(s) ofthe first electrode and/or of the injection needle, respectively, by adistance Δ₃₉ which is preferably greater than 1 mm, preferably greaterthan 2 mm, preferably greater than 3 mm, and/or preferably less than 8mm, preferably less than 7 mm, preferably less than 5 mm, preferablyless than 4 mm.

Advantageously, the guiding rods may be inserted in their respective rodinsertion guides 28 c before any penetration of an electrode needle ofthe first electrode and/or of the injection needle, respectively, intothe corresponding insertion guide 28 a or 28 b of the support. Thereforethe tip of the inserted needle may not prick into the inner surface ofsaid insertion guide 28 a or 28 b.

Preferably, the largest transversal dimension e₃₉ of a guiding rod 39,i.e. in a cross-section perpendicular to its length, is greater than 0.5mm, preferably greater than 0.8 mm, preferably greater than 0.9 mm,and/or less than 2.0 mm, preferably less than 1.5 mm, preferably lessthan 1.2 mm. Advantageously, the rigidity of the guiding rod isincreased and guidance is improved.

Preferably, the device comprises a needle stop, generally referenced as29, that is able to limit the movement of the electrode needle 14,referenced as 29 a, and/or of an injection needle, referenced as 29 b,and/or of a guiding rod 39, referenced as 29 c, during the stage ofpenetration into the eye.

In the close position represented in FIG. 3a , the needle stop 29 abutson the support 16 so as to define the insertion length of the needleinto the eye O.

A guiding rod stop 29 c is preferably rigidly fixed on the guidingrod(s) 39, as represented on FIG. 6 c.

The length of the part of an electrode needle and/or of an injectionneedle which may be inserted (insertion length) in the eye is determinedso that the tip of said electrode needle and/or injection needle may notreach the region of the virtual sphere which is opposite to theinsertion point of said needle.

Preferably, a needle stop 29 a (or 29 c if an electrode needle is guidedby a guiding rod, as in FIG. 6) is configured so that in a front view ofthe second electrode, i.e. when observing the second electrode along itsmain axis, the inserted electrode needle(s) extend, in a close position,so as to completely cross the electrode contact surface defined by thesecond electrode (i.e. extend in front of the electrode contact surfaceat least from one side to the opposite side of the electrode contactsurface).

A needle stop 29 preferably comprises wings 45 to make the handling ofthe needle stop easier (see FIG. 6c ).

A needle stop 29 a preferably comprise connectors 46 for the electricalconnection to a terminal of the generator. A connector 46 may comprise ascrew to press a wire electrically connected to said terminal on a partelectrically connected to the electrode needle(s). It may also comprisea socket electrically connected to the electrode needle(s) andconfigured to cooperate with a corresponding plug of a wire electricallyconnected to said terminal, such as a micro jack plug.

An insertion guide and the corresponding needle are preferablyconfigured so that, in the close position, the needle can only penetrateat a maximal depth, measured from the surface of the virtual sphere.

Preferably, the maximal depth p₄₂ for any injection needle is greaterthan 0.6 mm, preferably greater than 0.7 mm, preferably greater than 0.8mm, and/or less than 1.2 mm, preferably less than 1.1 mm, preferablyless than 1.0 mm (See FIG. 6e ).

Preferably, the maximal depth p₁₄ for an electrode needle, preferablyfor any electrode needle is greater than 1.3 mm, preferably greater than1.4 mm, preferably greater than 1.5 mm, preferably greater than 1.6 mm,and/or less than 2.1 mm, preferably less than 1.9 mm, preferably lessthan 1.8 mm, preferably less than 1.7 mm (See FIG. 6e ).

In an embodiment, the support is configured so that, in the closeposition, the depth of the tip 27 of an electrode needle and/or aninjection needle under the virtual sphere S defining the support contactsurface 18 is the same, independently from the insertion guide 28 aand/or 28 b, respectively, into which said electrode needle and/orinjection needle is introduced.

In an embodiment, the support is configured so that, in the closeposition, the position of the tip 27 of an electrode needle and/or aninjection needle, and in particular the insertion depth of the needle,depends on the insertion guide 28 a and/or 28 b, respectively, intowhich said needle is introduced.

Advantageously, the support may therefore be locally adapted to definedifferent insertion lengths and/or different orientations of theinsertion guides 28 a or 28 b, as represented in FIG. 3 a′.

A plurality of insertion guides may be used to enable different closepositions for a needle and/or to provide a single close position for afirst electrode or for injection means comprising several needles.

In particular, when the support comprises several electrode insertionguides 28 a, possibly with different lengths or orientations, theinsertion of corresponding electrode needles makes it possible achievingan optimal net of electrode needles.

If the electrode needle 14 is also an injection needle, thismultiplicity of different insertion guides advantageously allows for aplurality of injections at different points so as to very preciselydefine the region into which the product is to be injected.Advantageously, the region of the eye that an injection needle may reachis also enlarged.

Finally, this multiplicity of different insertion guides advantageouslyallows for the same support to be used for different applications ordifferent products.

The insertion guides are preferably rectilinear.

In an embodiment, the insertion guides 28 a and/or 28 b and/or 28 c areall parallel to each other.

In an embodiment, which is not preferred, when observed along the axisX, the insertion guide(s) 28, i.e. 28 a and/or 28 b and/or 28 cextend(s) substantially radially relatively to said rim (i.e. in a planecontaining the axis X, see the middle guide in FIG. 2b ), and inparticular extends along an insertion axis Δ₂₈ which makes, with adirection tangential to said rim and containing the point ofintersection of the insertion axis and of the rim 20, an angle θ₂₈,greater than 60°, greater than 70° and/or less than 110°, less than100°. In particular, an insertion guide may extend substantially in aplane containing the centre C of the spherical virtual sphere S andperpendicular to the circular rim 20, as represented in FIG. 3 a.

Preferably, the angle θ₂₈ is less than 45°, preferably less than 30°,preferably less than 20°, preferably less than 10°.

Preferably, an insertion guide, preferably any insertion guide extendsalong an insertion axis Δ₂₈ which defines an angle β less than 20°, lessthan 15°, less than 10°, less than 5°, less than 1° with a plane P₂₀containing said rim.

Preferably, an insertion guide, preferably any insertion guide extendsparallel to the plane P₂₀.

Preferably, at least one electrode insertion guide 28 a, preferably atleast the electrode insertion guide 28 a which is the closest to theplane P₂₀ of the rim 20, is conformed so that, in the close position, anelectrode needle 14 inserted in said electrode insertion guide 28 aextends at a distance d greater than 2 mm, preferably greater than 3 mm,preferably greater than 3.5 mm, preferably greater than 4 mm, and lessthan 6 mm, preferably less than 5 mm, less than 4.5 mm, from the planeP₂₀ of the rim 20 (i.e. the distance d applies to any point of theelectrode needle (See FIG. 4e )).

Preferably, at least one, preferably any electrode insertion guide 28 a,is conformed so that, in the close position, an electrode needle 14inserted in said electrode insertion guide 28 a completely extendsoutside the virtual cylinder Cy of axis X bearing on said rim (see FIG.3a ′).

Preferably, at least one, preferably any electrode insertion guide 28 a,is conformed so that, in the close position, the non insulated part 14 bof an electrode needle 14 inserted in said electrode insertion guide 28a extends, when observed along the axis X, at least partially,preferably completely within the area in front of the second electrode.

When the electrode contact surface is rectangular, the insertion axis ofan insertion guide, preferably of any insertion guide is preferablysubstantially parallel to one of the sides, preferably a large side, ofthe electrode contact surface.

In the case where the electrode needles are coplanar, the plane of theelectrode insertion guides is preferably substantially parallel to thelarge and/or small sides.

Preferably, an insertion guide 28, preferably any insertion guide 28extends substantially parallel to the general plane P₁₇ of the electrodecontact surface 17 of the second electrode.

Preferably, the insertion axis Δ₂₈ of an insertion guide 28, preferablyof any insertion guide, defines an angle with a plane perpendicular tothe main axis Δ₁₇ of the electrode contact surface 17, being less than50°, less than 30°, less than 20°, less than 10°, preferably less than5°, preferably substantially null, as represented in FIG. 4 e.

Preferably, when the electrode contact surface is spherical, at least aradius of said electrode contact surface 17 is included in a planeperpendicular to said insertion axis. Preferably, said radius crossessaid electrode contact surface about its centre.

Preferably, the electrode insertion guides 28 are configured so that, inthe close position, the distance δ between the invasive electrode needle14, preferably any invasive electrode needle, and the electrode contactsurface 17 is between 2.0 and 1.3 mm, preferably between 1.8 and 1.5 mm,preferably between 1.7 and 1.mm, preferably about 1.65 mm, andpreferably is substantially constant whichever point of the electrodecontact surface is being considered, as represented in FIG. 1b or FIG. 4e.

Preferably, at least two electrode insertion guides 28 a extend in acommon plane P_(28a). In a preferred embodiment, all the electrodeinsertion guides 28 a extend in the same plane P_(28a). Preferably, asrepresented in FIG. 4e , the plane P_(28a) defines with the plane P₂₀ ofthe rim 20 an angle Ω which is greater than 40°, greater than 45°,preferably greater than 50°, and/or less than 80°, preferably less than70°, preferably less than 60°, preferably less than 55°.

In an embodiment, the outlet orifices 30 and/or inlet orifices 32 of theelectrode insertion guides 28 a do not all extend at the same distancefrom the plane P₂₀ of the rim 20, as represented in FIG. 3a or FIG. 4 e.

Preferably, the plane P_(28a) extends substantially parallel to theelectrode contact surface which is intended to come into contact withthe outside surface of the eye. The angle between said plane P₂₈ and thegeneral plane in which the second electrode extends (plane perpendicularto the main axis of the second electrode), is preferably less than 20°,preferably less than 15°, preferably less than 10° or less than 5°.

Preferably, all the invasive electrode needles of the first electrode,preferably three, preferably four electrode needles, extend, in theservice position, in the plane P_(28a). Preferably, at any point of theelectrode contact surface 17 of the second electrode, the distance abetween the electrode contact surface 17 and the plane P₂₈ is between2.0 and 1.3 mm, preferably between 1.8 and 1.5 mm, preferably between1.7 and 1. mm, and is substantially constant whichever point of theelectrode contact surface is being considered (see FIG. 4e ).

The injection needle insertion guide(s) may have one or severalcharacteristics of the electrode insertion guides 28 a.

In an embodiment, the support comprises at least one, preferably aplurality of electrode insertion guides 28 a and at least one injectionneedle insertion guide 28 b configured to guide the insertion into theeye of electrode needle(s) and injection needle(s) along respectiveinsertion axis, wherein planes perpendicular to said respectiveinsertion axis define an angle greater than 3°, greater than 5°, and/orless than 10°. In other words, in the close position, the electrode andinjection needles are not inserted parallelly to each other.Advantageously, the electrode contact surface 17 of the second electrodecan be enlarged, without any deterioration of the mechanical resistanceof the support.

The support preferably comprises prepositioning guide(s) configured toguide one or several needles, i.e. electrode needle(s) and/or injectionneedle(s), into a position wherein said electrode needle(s) and/orinjection needle(s) is(are) in line with the axis of a correspondinginsertion guide.

Advantageously, the prepositioning of a needle allows for an alignmentof this needle with a corresponding insertion guide, so that during theinsertion, the tip of the needle will not contact the support andtherefore will not be blunted.

In particular, the support preferably defines prepositioning means whichmakes the insertion of the needle(s) into the inlet orifice(s) 32easier.

Preferably, as represented in FIG. 4e , the prepositioning meanscomprise a converging chute 33. The chute 33 comprises a large opening34 in which it is easy introducing the needle. The converging part ofthe chute 33 guides the needle until it reaches the bottom of the chute33. At this position, the tip of the needle faces an inlet orifice 32 sothat it may be introduced into the inlet orifice without any risk ofhitting the support when it is introduced into the inlet orifice 32.

In the embodiment of FIG. 4e , it is however necessary that the threeelectrode needles bear an inclined surface 35 of the chute 33.

Similar insertion guides and prepositioning means can be provided forthe electrode needle(s) and for the injection needle(s). In particular,as represented in FIGS. 4b and 5b , a chute 44 may be provided so thatan injection needle be aligned with an inlet orifice of an injectionneedle insertion guide 28 b.

The embodiment of FIG. 5 does not comprise a chute for the electrodeneedles, because of the guidance by the guiding rods 39 into the rodinsertion guides 28 c.

Pharmaceutical Composition

The injected product may be, in particular, any of the pharmaceuticalcompositions described in WO/2013/024436, incorporated by reference, andin particular a therapeutic nucleic acid of interest, preferably adesoxyribonucleic acid (DNA) molecule (cDNA, gDNA, synthetic DNA,artificial DNA, recombinant DNA, etc.) or a ribonucleic acid (RNA)molecule (mRNA, tRNA, RNAi, RNAsi, catalytic RNA, antisens RNA, viralRNA, etc.). In an embodiment, the composition contains a circular pieceof DNA.

In another particular embodiment, the electroporation device of theinvention is particularly suitable for performing gene replacement.Accordingly the nucleic acid may encode for a viable protein so as toreplace the defective protein which is naturally expressed in thetargeted tissue. Typically, defective genes that may be replacedinclude, but are not limited to, genes that are responsible for thediseases disclosed in WO/2013/024436.

Kit

In accordance with the present invention, kits are envisioned. A deviceaccording to the invention and a pharmaceutical composition according tothe invention, and optionally instructions for use may be suppliedtogether in a kit. Within the kit, the components may be separatelypackaged or contained.

Instructions can be in written, video, or audio form, and can becontained on paper, an electronic medium, or even as a reference toanother source, such as a website or reference manual.

Other components such as excipients, carriers, other drugs or adjuvants,instructions for administration of the active substance or composition,and administration or injection devices can be supplied in the kit aswell.

Method

The method of the invention may be used for treating an ocular diseasein a subject, the pharmaceutical composition being preferably chosenamong the pharmaceutical compositions which are described here above.

To use the electroporation device according to the first aspect of theinvention, an operator may proceed by the following steps:

First, the operator fixes the second electrode on the support, couples areservoir filled with the pharmaceutical composition to the injectionneedle, and electrically connects the first and second connectors to thetwo terminals of the electrical generator.

To position the device, the operator places the rim 20 on the limbus Liof the eye O. The placement of the rim 20 on the edge of the cornea andthe bearing of the spherical support contact surface 18 on the scleraguarantee a good stability of the device and a very precise positioning.The stabilisation is very important in the present specific application,since the angles between the electrode needles and/or injection needlein one hand, and the spherical support contact surface in the otherhand, are very low at the insertion points, i.e. the needles areinserted almost tangentially to this surface, which makes the insertiondifficult.

The operator then pushes the first electrode, preferably a comb ofelectrode needles, previously in a remote position, into the insertionguides 28 a.

In an embodiment, the guiding rods 39 penetrate into the correspondingrod insertion guides 28 c. In another embodiment, the guiding rods areslidably mounted on the support, and maintained on the support with oneor several rod stops, so that, advantageously, no insertion of a guidingrod 39 into the corresponding rod insertion guide is necessary.

They can then guide the movement of the first electrode, to make surethat the electrode needles easily enter into their correspondinginsertion guides 28 a, until the first electrode abuts on the outsidesurface 26 of the support 16, and therefore reaches the close position.The electrode needles then define a grid which extends substantiallyparallel to the second electrode, all along the length of the secondelectrode.

The inventors have shown that human eyes all have very similardimensions and shapes and, in particular, that the distance between theciliary muscle and the edge of the cornea of an eye is substantially thesame regardless of the individual concerned. The shape and arrangementof the first electrode and of the second electrode, of the insertionguides 28, of the pikes 26, of the rim 20, and of the spherical contactsurface are determined such that, in the close position, the operator isguaranteed that the first and second electrodes are in the optimalposition to create an electrical field particularly effective forelectroporation into the ciliary muscle.

The operator then inserts the injection needle in the correspondinginsertion guide, until a corresponding close position. The previousinsertion of the electrode needles enables a very stable position of thesupport during the insertion of the injection needle.

In an embodiment, the stop of the injection needle determining its closeposition is determined for the ejection orifice(s) to open in theciliary muscle, in front of the grid of the electrode needles.

The operator can then inject the composition.

In a preferred embodiment, the injection needle is part of a syringe andthe operator put the injection needle in the chute 44 so that it facesthe inlet orifice of the injection needle insertion guide. The operatorthen inserts the injection needle through the injection needle insertionguide 28 b, in the space between the first and second electrodes,injects the composition and then withdraws the injection needle from theeye.

Multiplication of the injection points promotes the penetration of thecomposition.

The device is then in the service position and the operator sends asuitable electrical signal, for example suitable electrical impulses, bymeans of the electrical generator, in such a way as to create, withinthe injection zone, an electrical field that promotes electroporation.The above described configuration of the device, and in particular witha flattened shape for the electrode needle(s), improves theelectroporation efficiency.

In a particular embodiment, an electrical field constituted by one ormore electrical pulse(s) is applied.

The field intensity of which is preferably between about 1 and 600Volts, preferably 1 and 400 Volts, even more preferably between about 1and 200 Volts, advantageously between about 10 and 100 Volts, or 15 and70 Volts.

The total duration of application of the electric field may be between0.01 millisecond and 1 second, preferably between 0.01 and 500milliseconds, more preferably between 1 and 500 milliseconds, even morepreferably greater than 1 or 10 milliseconds. In a preferred embodiment,the total duration of application of the electric field is between 10milliseconds and 100 milliseconds and is preferably of 20 milliseconds.

The number of electric pulses applied may be between for example 1 and100 000. Their frequency may be comprised between 0.1 and 1000 Hertz. Itis preferably a regular frequency.

Electric pulses may also be delivered in an irregular manner relative toeach other, the function describing the intensity of the electric fieldas a function of the time for one pulse being preferably variable.

Electric pulses may be unipolar or bipolar wave pulses. They may beselected for example from square wave pulses, exponentially decreasingwave pulses, oscillating unipolar wave pulses of limited duration,oscillating bipolar wave pulses of limited duration, or other waveforms. Preferentially, electric pulses comprise square wave pulses oroscillating bipolar wave pulses.

When the electroporation of the product has been completed, the operatorelectrically disconnects the electrodes and the generator.

As will now be clear, the device according to the invention permits

-   -   precise and stable positioning of the electrodes;    -   precise guidance of the invasive electrode needle during its        penetration into the eye;    -   precise injection into the eye relative to the limbus;    -   the generation of an efficient homogeneous large electrical        field.

Of course, the invention is not limited to the embodiments described andshown, which have been provided by way of illustration. In particular,the various embodiments could be combined.

1. An electroporation device for injecting a product into a ciliarymuscle of an eye, said device comprising: a support having a sphericalsupport contact surface extending along a virtual sphere having a radiusbetween 10 and 15 mm, a first electrode comprising a curved invasiveelectrode needle, a second electrode having an electrically conductiveelectrode contact surface, an injection needle.
 2. The electroporationdevice according to claim 1, the support comprising an insertion guideconfigured to guide a sliding of said electrode needle and/or injectionneedle along a respective insertion axis, so that the angle ω betweensaid insertion axis and a plane P_(S) tangential to the virtual sphereat the insertion point is less than 40°, the insertion point being thepoint where said insertion axis crosses said virtual sphere.
 3. Theelectroporation device according to claim 2, wherein the angle betweensaid insertion axis and a plane perpendicular to the main axis of theelectrode contact surface is less than 5°, the “main axis” of a surfacebeing the direction perpendicular to said surface passing through itscentre.
 4. The electroporation device according to claim 2, wherein thesupport comprises at least two electrode insertion guides which extendin a common plane which defines, with a plane perpendicular to the mainaxis of the electrode contact surface an angle less than 5°.
 5. Theelectroporation device according to claim 1, wherein the support definesa circular rim, having an axis X and a radius of greater than 5 mm andof less than 8 mm, so as to match the limbus of the eye.
 6. Theelectroporation device according to claim 2, wherein the insertion axisdefines, at the insertion point, an angle α less than 50° with a planetangential to a cylindrical surface of axis X containing the insertionpoint and having a circular base.
 7. The electroporation deviceaccording to claim 6 wherein the insertion guide extends along aninsertion axis which defines an angle β less than 20° with a planecontaining said rim.
 8. The electroporation device according to claim 2,wherein the support comprises at least two electrode insertion guides,all the electrode insertion guides extending parallel to each other in acommon plane which defines with the plane of the rim an angle Ω which isgreater than 40° and/or less than 80°.
 9. The electroporation deviceaccording to any claim 5, wherein said rim is interrupted by at leastone notch.
 10. The electroporation device according to claim 9, saidnotch being located in a portion of the rim which extends along anangular sector less than 120° and centred on a median plane of thesecond electrode.
 11. The electroporation device according to claim 10,said notch being configured so that the limbus of the eye is visiblethrough the notch when positioning the support onto the eye.
 12. Theelectroporation device according to claim 2, wherein the insertion guideis configured so that, in a position corresponding to a full insertionof said electrode needle, the distance between the electrode needle andthe electrode contact surface is between 2.0 and 1.3 mm.
 13. Theelectroporation device according to claim 1, wherein the length of saidelectrode needle is determined so that, when observing the secondelectrode along a direction perpendicular to said second electrode andpassing through its centre, the electrode needle extends, in a positioncorresponding to a full insertion of said electrode needle, so as tocompletely cross the electrode contact surface.
 14. The electroporationdevice according to claim 1, wherein the surface area of the electrodecontact surface is greater than 6 mm² and less than 20 mm².
 15. Theelectroporation device according to claim 1, wherein the electrodecontact surface extends on the same virtual sphere as the supportcontact surface.
 16. The electroporation device according to claim 1,wherein the first electrode and/or the injection needle comprises atleast one guiding rod, extending parallel to the electrode needle(s)and/or to the injection needle, respectively, and the support comprisescorresponding rod insertion guide(s).
 17. The electroporation deviceaccording to claim 1, wherein the support comprises prepositioningguide(s) configured to guide an electrode needle and/or an injectionneedle into a position wherein said electrode needle and/or saidinjection needle is(are) in line with an axis of a correspondinginsertion guide.
 18. The electroporation device according to claim 1,wherein, in a position corresponding to a full insertion of theinjection needle, the maximal depth of the injection needle under thevirtual sphere is between 0.8 mm and 1.0 mm, and wherein, in a positioncorresponding to a full insertion of the electrode needle, the maximaldepth of the electrode needle under the virtual sphere is between 1.5 mmand 1.8 mm.
 19. An electroporation device for injecting a product into aciliary muscle of an eye, said device comprising: a support having aspherical support contact surface extending along a virtual spherehaving a radius between 10 and 15 mm, a first electrode comprising aninvasive electrode needle, a second electrode having an electricallyconductive electrode contact surface, an injection needle, wherein thesupport defines a circular rim having an axis X and a radius of greaterthan 5 mm and of less than 8 mm, so as to match the limbus of an eye,said rim being interrupted by at least one notch.
 20. An electroporationdevice for injecting a product into a ciliary muscle of an eye, saiddevice comprising: a support having a spherical support contact surfaceextending along a virtual sphere having a radius between 10 and 15 mm, afirst electrode comprising an invasive electrode needle, a secondelectrode having an electrically conductive electrode contact surface,an injection needle, wherein the electrode needle extends in front ofthe electrode contact surface, substantially parallelly to the electrodecontact surface, the support comprising an insertion guide configured toguide a sliding of said electrode needle and/or injection needle along arespective insertion axis, and in a position corresponding to a fullinsertion of said electrode needle, the distance between the electrodeneedle and the electrode contact surface is between 2.0 and 1.3 mm.